PROJECT SUMMARY/ABSTRACT The benefit of adding oxaliplatin to the standard 5-fluorouracil-based chemotherapeutic regimen for colorectal cancer patients was demonstrated by a number of randomized controlled trials that reported improved disease- free and overall survival. However, the major dose-limiting side effect of this therapy is oxaliplatin-induced peripheral neuropathy (OIPN), which affects a large proportion of treated patients. OIPN can be acute, occurring during or immediately after oxaliplatin infusion, or chronic, which can occur between infusions as well as after completing treatment. Acute symptoms are typically mild whereas chronic OIPN is more debilitating, usually presenting as bilateral, distal neuropathy with symptoms that include neuropathic pain, numbness/ tingling, and sensory ataxia. These symptoms interfere with activities of daily living and are associated with a number of injuries/morbidities including falls, psychiatric disturbances, and sleep disorders?all of which significantly impair colorectal cancer survivors? quality of life. A number of NCI-sponsored trials were launched in an attempt to find therapies that could prevent and/or treat chemotherapy-induced peripheral neuropathy (CIPN). As a result of these trials, only one drug, duloxetine, is currently recommended to treat CIPN; there are no recommended preventive therapies. However, other drugs/therapies have shown promise in small studies but have not been recommended due to a lack of scientific rigor. Observational comparative effectiveness research utilizing the Surveillance, Epidemiology, and End Results database combined with Medicare claims (SEER-Medicare) is able to leverage large amounts of patient sociodemographic, treatment, and clinical data with long-term follow-up. These studies overcome the small sample size and limited follow-up limitations of clinical trials and can provide new information on treatment effectiveness for several understudied, potentially effective therapies. In this study, we will use the SEER-Medicare database to provide new evidence on the effectiveness of preventive and treatment options for OIPN in stage II-IV colorectal cancer patients and identify sociodemographic/clinical characteristics of patients that increase/decrease the likelihood of OIPN diagnosis over time. We will evaluate the ability of venlafaxine, duloxetine, and oxcarbamazepine to prevent OIPN. For treatment of OIPN, we will evaluate the potential superiority of venlafaxine, nortriptyline, gabapentin/pregabalin, transcutaneous electrical nerve stimulation, spinal cord stimulation, and opioids compared to duloxetine. Additional therapies will also be evaluated. Effectiveness of therapy will be assessed by the ability to prevent/resolve OIPN and reduce OIPN-related outcomes. Lastly, to provide new insight concerning the etiology of OIPN, we will evaluate sociodemographic and clinical characteristics of patients that increase/decrease the likelihood of early and long-term OIPN. The results of this study are critically needed to provide new therapeutic options to prevent and treat OIPN for the large number of colorectal cancer survivors suffering from this debilitating consequence of oxaliplatin chemotherapy.